Preparation of α-substituted β-dicarbonyl and β-cyanocarbonyl compounds

ABSTRACT

β-Dicarbonyl and β-cyanocarbonyl compounds ##STR1## where R 1  is alkyl of 1-20 carbons, X is --COR 2 , Y is --COOR 3 , --COR 3  or --CN, and R 2  and R 3  are each C 1  -C 10  -alkyl, are prepared from R 1  --CHO (II) and X--CH 2  --Y (III) by reaction in the presence of a condensation catalyst, hydrogen and a hydrogenation catalyst, using an oxide or phosphate of Mg, Al, Ti, Zn or a rare earth metal as the condensation catalyst.

This application is a division of application Ser. No. 782,615, filedOct. 1, 1985, which application has now issued as U.S. Pat. No.4,684,743, which was a continuation of Ser. No. 666,477, filed Oct. 30,1984, abandoned, which is a continuation-in-part of application Ser. No.515,880, filed July 21, 1983, and now abandoned.

The present invention relates to an improved process for the preparationof α-substituted β-dicarbonyl and β-cyanocarbonyl compounds of thegeneral formula I ##STR2## where R¹ is hydrogen or an organic radical, Xis --COR² and Y is --COOR³, --COR³ or --CN, where R² and R³ are each C₁-C₁₀ alkyl, by reacting an aldehyde II

    R.sup.1 --CHO                                              II

with a compound III ##STR3## in the presence of a conoensation catalyst,hydrogen and a hydrogenation catalyst.

The reaction of carbonyl compounds, including aldehydes II, withcompounds III to give condensation products IV ##STR4## is generallyknown as the Knoevenagel reaction (cf. eg. "Organikum" VEB DeutscherVerlag der Wissenschaften, 1962, page 442). It is carried out in theliquid phase using various basic or acidic, usually homogeneous,catalysts and continuously removing the water of reaction formed.

German Published Application DAS No. 2,060,443 also discloses aprocedure in which the Knoevenagel reaction is carried out in thepresence of hydrogen and a hydrogenation catalyst so that compounds Iare obtained directly.

Finally, British Pat. No. 1,014,273 discloses a procedure in which thealdol condensation of propionaldehyde is carried out under hydrogenatingconditions by means of solid condensation catalysts, such as oxides andphosphates, including those proposed herein as condensation catalysts,to give 2-methylvaleraldehyde.

However, the condensation catalysts recommended for the Knoevenagelreaction are usually particularly suitable only for certain cases, sothat different instructions and equipment are always required for thepreparation of different compounds I. This obviously prevents efficientpreparation of various compounds I which, as special products, are as arule required in only limited amounts. Moreover, undesirabledecarboxylation frequently takes place as a side reaction in the case ofcompounds III or I in which one or more of X and Y is --COOR², andfinally, the use of homogeneous catalysts involves additionalexpenditure for removing them from the reaction mixtures formed.

It is an object of the present invention to remedy these deficiencies bymeans of a universally applicable heterogeneously catalyzed processwithout having to accept disadvantages such as undesirable sidereactions or reduced yields.

We have found that this object is achieved and that the compounds Idefined above are obtained in a technologically advantageous manner fromthe compounds II and III, also defined above, in the presence of acondensation catalyst, hydrogen and a hydrogenation catalyst by using anoxide or phosphate of magnesium, aluminum, titanium, zinc or a rareearth metal as the condensation catalyst.

We have also found that particularly good results are obtained usingaluminum oxide as the condensation catalyst.

The solid catalyst components, ie. the hydrogenation catalyst and thecondensation catalyst, can in principle be used separately, but it isusually advisable to use a mixed catalyst of from 0.1 to 50% by weightof the hydrogenating component and from 50 to 99.9% by weight of thecondensing component.

If a noble metal, especially palladium, is used as the hydrogenationcatalyst, the mixed catalyst is advantageously prepared conventionally,by processing the pulverulent condensation catalyst to a paste with anaqueous solution of a salt of one of the noble metals, the amount andconcentration of the salt solution corresponding to the desired catalystcomposition. This paste is then processed to catalyst particles, forexample to beads from 1 to 10 mm in diameter or cylinders from 0.5 to 5mm in diameter and from 1 to 10 mm in height, after which theseparticles are dried and heated at from 150° to 1,000° C. under ahydrogen atmosphere, whereupon the noble metal salt is reduced to themetal.

It is also possible to apply the paste to an inert carrier, eg. silicicacid, and to produce a supported catalyst in a conventional manner.

Palladium is the preferred hydrogenation catalyst and aluminum oxide isthe preferred condensation catalyst. Of the Al₂ O₃ modifications, thosewith a high specific surface area, ie. the γ-form (from 85 to 400 m² /g)and the η-form (from 100 to 600 m² /g), are particularly preferred.α-Al₂ O₃ (from 40 to 70 m² /g) is also suitable but requires somewhatlonger reaction times.

Particularly suitable oxides and phosphates of rare earth metals arethose of cerium, praseodymium and neodymium. A mixture of from 1 to 10%by weight of compounds of rare earth metals and from 90 to 99% by weightof another oxide or phosphate conforming to the above definition, inparticular Al₂ O₃, is preferably used.

In principle, any desired amount of catalyst can be used for thereaction according to the invention, since it only influences the rateof reaction. However, for technological reasons, the amount shouldadvantageously not exceed 0.4 kg per kg of the mixture of II and III,and it should generally be not less than 0.01 kg per kg of the mixtureof II and III in order to achieve economic space/time yields.

Apart from the solid catalyst, the reaction is preferably carried out inthe liquid phase, ie. both the starting substances II and III and theproduct should be virtually completely in the liquid phase. If one ofthe substances is solid under the reaction conditions, a solvent is alsoused, but if the substances are all liquid and miscible with oneanother, it is not necessary to use a solvent unless advantageous forother reasons, for example because the starting substances are alreadyavailable in dissolved form or because working up is thereby simplified.

Suitable solvents are inert liquids, for example chlorinatedhydrocarbons, eg. methylene chloride, aromatic hydrocarbons, eg.toluene, ethers, eg. tetrahydrofuran and dioxane, and C₁ -C₄ -alcoholswhich do not give rise to any noticeable degree of trans-esterification(X and Y are --COOR²).

The reaction is preferably carried out under an H₂ pressure range offrom 1 to 50 bar at from 25° to 180° C., usually under an H₂ pressure offrom 1 to 10 bar and at 50° and 150° C., depending on the reactivity ofthe starting compounds II and III.

Equimolar amounts of II and III are advantageously used. If II ispresent in excess, self-condensation of the excess amount is to beobserved in certain circumstances, and if III is present in excess, twoadduct formations with II can take place, with elimination of water.

However, observations have so far shown that the side reactions causedby the presence of water or an excess of one of the starting substancesare of minor significance, since the main reaction (adduct formation ofII with III, followed by dehydration and hydrogenation) proceeds morerapidly than the side reactions. It should therefore merely be ensuredthat the times for the main reaction are not substantially exceeded,which, needless to say, is self-evident.

The process according to the invention can be carried out continuouslyor batchwise in a conventional manner and in principal does not dependon the nature of the starting compounds II and III.

Examples of aldehydes II are:

aliphatic aldehydes of 1 to 20 carbon atoms, especially C₁ -C₂₀-alkanals; formaldehyde is advantageously used in the solid polymericform, for example as paraformaldehyde;

cycloaliphatic aldehydes which are derived from 5-membered or 6-memberedcyclic compounds;

araliphatic aldehydes, eg. phenylacetaldehyde;

isocyclic aromatic aldehydes which are derived from benzene or morehighly fused ring systems thereof; and

heterocyclic aromatic aldehydes, eg. the pyridinealdehydes or thethiopheneladehydes.

These aldehydes may contain substituents, eg. halogen, cyano, nitro ordisubstituted amino, and heteroatoms or groupings, eg. oxygen, sulfur or--CO--O--.

If the aldehydes contain reactive groups or groupings, these may bemodified under certain circumstances, but without affecting theprinciple of the reaction according to the invention. Thus, anunsaturated aldehyde, eg. acrolein or a derivative I of this aldehyde,may be hydrogenated, but it is possible to promote or suppress thehydrogenation by conventional hydrogenation techniques. The character ofan unsaturated radical R¹ is, however, generally retained because thedouble bond formed by the condensation reaction is greatly activated byX and Y is therefore preferentially hydrogenated.

The reaction principle of course also applies to polyvalent aldehydes,eg. to terephthalaldehyde, providing interesting possibilities for thesynthesis of compounds I containing two or more --CH(X)Y groupings inthe molecule.

Compounds III, of which the characteristic feature is the activatedmethylene group between X and Y, include:

C₁ -C₁₀ -alkyl esters of malonic acid, especially the methyl and ethylester,

esters of acetoacetic acid, especially C₁ -C₁₀ -alkyl esters, preferablythe methyl and ethyl ester,

acetylacetone and higher homologs thereof where the acyl radical is ofnot more than 10 carbon atoms,

C₁ -C₁₀ -alkyl esters of cyanoacetic acid, especially the methyl andethyl ester,

acylacetic acid nitriles where acyl is of not more than 10 carbon atoms,especially acetoacetonitrile, and

malodinitrile.

Compounds III with a --CO--CH₂ --CO-- grouping in which the acyl groupsare linked to form a ring, as in cyclopentane-1,3-dione, are alsosuitable.

The process according to the invention substantially simplifiessynthesis of the compounds I, which are used as intermediates for othersyntheses, especially for those of drugs. Thus, the ethyln-butylcyanoacetate which can be obtained from n-butyraldehyde and ethylcyanoacetate is an intermediate for the known analgesic phenylbutazone.

EXAMPLES Examples A to J

Preparation of various catalysts

In each case 100 g of a pulverulent material used as a condensationcatalysts were mixed to a paste with 100 ml of aqueous palladium nitratesolution and cylindrical particles 2 mm in diameter and 5 mm in heightwere shaped from the paste. The particles were dried and heated at 500°C. under a hydrogen atmosphere for 6 hours, whereupon the Pd was reducedto the metal. The aqueous Pd nitrate solution always contained an amountof the salt corresponding to the composition of the catalyst.

Table 1 shows the characteristics of the catalysts thus prepared:

                  TABLE 1                                                         ______________________________________                                                   Condensing components                                                                         Pd content                                         Catalyst   [g]             % by weight                                        ______________________________________                                        A          γ-Al.sub.2 O.sub.3, 100                                                                 2.00                                               B          "               0.75                                               C          "               0.50                                               D          "               1.00                                               E          γ-Al.sub.2 O.sub.3, 95; Pr.sub.2 O.sub.3,                                               0.75                                               F          CepO.sub.4, 100 0.50                                               G          Dy.sub.2 O.sub.3, 100                                                                         1.00                                               H          ZnO, 100        0.50                                               I          Zn.sub.3 (PO.sub.4).sub.3, 100                                                                0.50                                               J          α-Al.sub.2 O.sub.3, 100                                                                 10.00                                              ______________________________________                                    

Examples 1 to 18

Preparation of various compounds I

In each case a g of an aldehyde II, b g of a compound III and c g of oneof the catalysts A to J were heated at T°C under a hydrogen pressure ofp bar in an autoclave for t hours. The amounts of a and b were alwaysequimolar relative to one another. Conventional distillative working upof the reaction mixture which remained after removal of the catalyst andthe water of reaction gave a yield of y % of the desired compound I.

The experimental conditions and results are summarized in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Exam-                            cat.                                                                             t  p  T  compound I     y                 ple aldehyde II                                                                             [g] compound III                                                                            [g]  [g]                                                                              [h]                                                                              [bar]                                                                            [°C.]                                                                     B.p. [°C./mbar]                                                                       [%]               __________________________________________________________________________    1   n-butanal 535 ethyl cyano-                                                                            840  A 40                                                                              7 20 70 ethyl n-butylcyanoacetate                                                                    95                                  acetate                    124-126/20                       2   propanal  52.2                                                                              acetylacetone                                                                           90   B 7                                                                               6 20 75 3-propylpentane-2,4-dione                                                                    93                                                             102-110/20                       3   n-butanal 50.4                                                                              methyl    81   C 6                                                                               8 35 80 methyl n-butyl-                                                                              92                                  acetoacetate               acetoacetate 102/10              4   n-octanal 256 methyl    232  C 20                                                                              3 15 70 methyl n-octyl-                                                                              90                                  acetoacetate      +3 25 80 acetoacetate  93-95/0.3          5   2-phenyl- 134 ethyl cyano-                                                                            113  D 20                                                                              2 20 50 ethyl 2-cyano-4-                                                                             85                    propanal      acetate           +2 35 90 phenylpentanoate;                                                             128-132/0.2                                                          +2 45 130                                 6   methoxy-  82  ethyl cyano-                                                                            113  B 10                                                                              2 15 50 ethyl 2-cyano-4-methoxy-                                                                     91                    acetaldehyde  acetate           +2 20 75 butyrate 128-132/22                                                  +2 25 100                                 7   parafor-  150 diethyl   800  C 50                                                                              2 15 70 diethyl methylmalonate                                                                       83                    maldehyde     malonate          +2 35 96 101-108/30                                                           +2 35 100                                 8   iso-butanal                                                                             57.6                                                                              ethyl cyano-                                                                            90   E 6                                                                               2 20 70 ethyl 2-cyano-4-methyl-                                                                      90                                  acetate           +2 40 110                                                                              pentanoate; 135/22                                                   +2 55 130                                 9   n-hexanal 200 diethyl   320  E 25                                                                              2 25 70 diethyl n-hexyl                                                                              78                                  malonate          +2 45 110                                                                              malonate 91-100/0.3                                                  +2 55 130                                 10  acetaldehyde                                                                            48.4                                                                              ethyl cyano-                                                                            113  C 20                                                                              6 50 40 ethyl ethylcyano-                                                                            70                                  acetate                    acetate 50-60/0.3                11  n-butanal 720 acetyl-   1000 C 70                                                                              3 30 70 n-butylpentane-2,4-dione                                                                     89                                  acetone           +3 35 80 100-105/28                       12  3-formyl- 332 ethyl cyano-                                                                            226  B 50                                                                              3 35 70 ethyl pin-3-yl                                                                               90thyl-               pinane        acetate           +3 40 75 cyanoacetate; 110/0.1                 ##STR5##                                                                                                               ##STR6##                        13  propanal  29  malodinitrile                                                                           33   F 5                                                                               8 50 35 n-propylmalodinitrile                                                                        70                14  n-butanal 50.4                                                                              methyl aceto-                                                                           81   G 6                                                                               8 35 80 methyl n-butylacetoacetate                                                                   80                                  acetate                                                     15  n-butanal 535 ethyl cyano-                                                                            840  H 40                                                                              7 20 70 ethyl n-butylcyanoacetate                                                                    80                                  acetate                                                     16  n-butanal 535 ethyl cyano-                                                                            840  I 40                                                                              7 20 70 ethyl n-butylcyanoacetate                                                                    82                                  acetate                                                     17  n-butanal 535 ethyl cyano-                                                                            840  J 50                                                                              12                                                                               1 70 ethyl n-butylcyanoacetate                                                                    90                                  acetate                                                     18  propanal  29  cyclohexane-                                                                            56   C 3                                                                               10                                                                              40 60 n-propylcyclohexane-2,6-dione                                                 2              75                                  1,3-dione in                                                                  20 ml of methanol                                           __________________________________________________________________________

We claim:
 1. A process for the preparation of an α-substituted compoundof the formula I ##STR7## where R¹ is alkyl of 1-20 carbons, Y is--COOR³, --CO--R³ or --CN, where R² and R³ are each C₁ -C₁₀ -alkyl,which process comprises: reacting an aldehyde II

    R.sup.1 --CHO                                              II

wth a compound III ##STR8## where R¹, R² and Y have the meanings setforth above, in the liquid phase at a temperature of 25° to 180° C. inthe presence of hydrogen, a noble metal hydrogenation catalyst and acondensation catalyst consisting essentially of an oxide or phosphate ofmagnesium, aluminum, titanium, zinc or a rare earth metal, said reactiontaking place in the essential absence of a homogeneous catalystcomponent.
 2. The process of claim 1, wherein a mixed catalyst of thematerial of the condensation catalyst and a noble metal of group VIII ofthe periodic table is used.
 3. The process of claim 1, wherein palladiumis used as the noble metal.
 4. The process of claim 1, wherein γ-Al₂ O₃or η-Al₂ O₃ is used as the condensation catalyst.